Acute exacerbation of asthma (AEA) or status asthmaticus is a long-lasting and severe asthma episode that is typically not responsive to bronchodilator or corticosteroid therapy. An AEA may be diagnosed, for example and without limitation, by the symptoms of dyspnea and bronchospasm. Patients often experience progressively worsening breathlessness, cough, wheezing, and chest tightness, or some combination of these symptoms of AEA.
Current standard of care (SOC) for AEA treatment relies on using low flow oxygen, inhaled β-agonists (e.g., albuterol), anticholinergics (ipratropium), and/or intravenous or oral corticosteroids (e.g., prednisone and methylprednisolone); intravenous (IV) magnesium may be included. In some countries or at some points in time, IV or subcutaneous (SC) adrenoceptor agonists (e.g., epinephrine in adults and terbutaline in children) and IV aminophylline may also be administered, but are not generally recommended at least for adults according to the current NAEPP Asthma Guidelines (2007). See; also, S. C. Lazarus NEJM Aug. 19, 2010; G. J. Browne et al. Lancet (1997) 349:301). Moreover, these treatments may not produce a significant clinical benefit and/or may provoke unwanted cardiovascular side-effects (e.g., tachycardia) when added to SOC. Although subcutaneous adrenalin or terbutaline in conjunction with nebulized albuterol and corticosteroid and aminophylline were reported over 20 years ago (M. A. Spiteri et al, Thorax (1988) 43:19-23) to provide some breathing benefit without undue side effects, such parenteral beta-agonist therapy has proven over the years to be too risky—especially from a cardiovascular liability standpoint—for limited observed benefit.
Recently, D. S. Wheeler et al. Pediatr. Crit. Care Med. (2005) 6:142-7 showed that terbutaline added to SOC in children with status asthmaticus did not provide a significant improvement in clinical asthma score or ICU stay. A reanalysis of data by G. J. Browne et al. Pediatr. Crit. Care Med. (2002) 3(2) led these authors to conclude that a single-dose intravenous salbutamol bolus in the initial treatment of children with acute severe asthma in the emergency department has the potential to shorten the duration of severe attacks and reduce overall requirements for inhaled salbutamol maintenance. However, a review conducted by A. H. Travers et al. Chest (2002) 122:1200-1207 of publications, which described randomized controlled trials comparing the use of IV β2-agonists versus placebo or SOC, led these authors to conclude that “[e]vidence is lacking to support the use of IV β2-agonists in [emergency department] patients with severe acute asthma. Moreover, the clinical benefit appears questionable, while the potential clinical risks are obvious. The only recommendations for IV β2-agonist use should be in those patients in whom inhaled therapy is not feasible, or in the context of a controlled clinical trial comparing IV β2-agonists with standard care vs standard care alone.” Hence, there appears to be little agreement in the literature as to the potential benefits of β-agonists administered intravenously. There may also be questions surrounding the merits of intravenous administration in children versus adults, who are suffering from a acute severe asthma attack and present themselves in an emergency department setting.
Although the results of a study by Appel et al. J. Allergy Clin. Immunol. (1989) 84:90-98 do not clearly define the role of systemic β-agonists in the treatment of life-threatening asthma, it suggests that subcutaneous administration of epinephrine or terbutaline should be considered in patients unresponsive to continuous nebulized β2-agonists, and in those patients unable to cooperate due to alteration of mental status or an inability to tolerate inhaled therapy. Epinephrine may also be delivered in intubated patients not responding to inhaled therapy during mechanical ventilation. Subcutaneously, 0.3-0.5 mL (1:1000) of epinephrine can be administered every 20 min. to a maximum of three doses. Terbutaline can be administered subcutaneously (0.25-0.5 mg) and is the preferred treatment in pregnant females.
Intravenous infusion of terbutaline starting at 0.05-0.10 μg/kg per min has been utilized predominantly in pediatric patients. It may be considered in the treatment of patients with no response to inhaled or subcutaneous treatment, and in whom respiratory arrest is imminent, or in patients not adequately ventilated despite optimal setting of the ventilator. A recent double blind, randomized controlled trial by Bogie et al. Pediatric Emergency Care (2007) 23(6) evaluated the benefit of intravenous terbutaline in 49 nonventilated children with acute severe asthma who were already on continuous high-dose nebulized albuterol. Although the use of intravenous terbutaline was associated with improvement in the clinical asthma severity score over the first 24 h, shorter use of continuous nebulized albuterol, and shorter ICU stay, the differences were not statistically significant.
The Applicants have identified novel methods for the treatment of severe asthma attacks, including AEA, especially in patients who fail to respond to current SOC. The Applicants have also discovered that bronchodilation and the reduced hospitalization of patients suffering from such attacks can be achieved by administering MN-221 or pharmaceutically acceptable salts thereof (collectively, Active Agent, as described further below). The discovery that Active Agent is particularly beneficial in treating patients suffering from an acute severe respiratory attack could not have been predicted from the clinical experience of those of ordinary skill in the art using known beta-agonists. Moreover, the Applicants' believe that their discoveries have special utility in treating an “exacerbation-prone” subset of asthmatics, who are at a higher risk of experiencing an acute exacerbation of asthma (for a discussion of this subset of asthmatics see, R. H. Dougherty Clin. Exp. Allergy. (2009) 39:193).